Dual Checkpoint Blockade Holds Promise as Long-term Treatment Option in NSCLC

Supplements And Featured PublicationsThe Current and Future State of Immune Checkpoint Inhibitors in NSCLC
Volume 01
Issue 01

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Stephen V. Liu, MD and Neal E. Ready, MD, PhD, discuss the new data with nivolumab plus ipilimumab in treatment-naïve NSCLC and provide commentary on treatment considerations for patients who are eligible to receive these regimens.

Stephen V. Liu, MD

Stephen V. Liu, MD

Biomarker selection has played a crucial role in the rapid advancement of clinical benefit observed for patients with non–small cell lung cancer (NSCLC). At the time of diagnosis of advanced lung cancer molecular testing is imperative and the best marker to have data for is PD-L1, according to Neal E. Ready, MD, PhD.

“We can now identify the right treatment for the right patient [and] I know that there’s a tendency to want to have one-size-fits-all treatment,” Ready said during a recent OncLive® Seminar Series. “For [patients with] PD-L1–low expressing tumors, we have a certain set of possible treatments [and] for PD-L1–high expressing tumors [there are] different options including monotherapy and other approaches.”

Immunotherapy treatment options for patients with NSCLC with PD-1 or PD-L1 inhibitors have demonstrated durable responses with longer-term follow-up. In addition to monotherapy, chemoimmunotherapy treatment options have expanded the armamentarium for these patients. “We have a lot of different options depending on histology and, presumably, more to come,” said Stephen V. Liu, MD, who joined Ready in the seminar.

“The other category we have is dual checkpoint blockade [using] 2 different checkpoint inhibitors: one targeting PD-1 and the other targeting CTLA4. Both play an important role in priming immune cells,” Liu continued.

CheckMate 227 (NCT02477826) and CheckMate 9LA (NCT03215706) evaluated the immunotherapy combination of nivolumab (Opdivo), a PD-1 inhibitor, and ipilimumab (Yervoy), a CTLA-4 inhibitor, for patients with treatment-naïve NSCLC.1-4 Updated findings for both trials, 5- and 3-year data, respectively, were presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting (Tables 1 and 2).1,2

Table 1. Long-Term Efficacy Outcomes in CheckMate 2271

Table 1. Long-Term Efficacy Outcomes in CheckMate 2271

Table 2. Long-Term Efficacy Outcomes in CheckMate 9LA2

Table 2. Long-Term Efficacy Outcomes in CheckMate 9LA2

During the seminar, Ready and Liu discussed the new data and provided commentary on treatment considerations for patients who are eligible to receive these regimens.

Steven V. Liu, MD: The combination of nivolumab and ipilimumab has [been shown] to be very effective in melanoma [and] some early success was observed in lung cancer including small cell lung cancer. CheckMate 227 was a bit of a complicated study. It was for patients with advanced NSCLC who had no prior therapy and excluded [patients with] EGFR and ALK mutations. Patients with squamous and nonsquamous histologies were stratified and this split up [the trial] into almost 2 different studies.

If a patient had PD-L1 expression of 1% or greater they were randomly assigned to nivolumab and ipilimumab plus standard chemotherapy or nivolumab alone, whereas if they had PD-L1–negative disease [they were randomly assigned to one of] 3 arms; nivolumab/ipilimumab, chemotherapy alone, or a third arm that was nivolumab with chemotherapy. The thought here was that giving nivolumab alone to [a patient with] PD-L1–negative disease was not well advised.

The primary end point was observed in data from the PD-L1positive subgroup and that’s going to have important implications in how we interpret [these data] and maybe, more importantly, how the regimen was approved. Dr Ready, you were involved in the early studies. [Please discuss the] decision to focus on the PD-L1positive group.

Neal Ready, MD, PhD: In the phase 1 trial [CheckMate 012; NCT01454102] we established that the full dose of nivolumab and ipilimumab 1 mg/kg was safe in patients with lung cancer. Because it was a phase 1 trial, we included patients with actionable alterations. Among the 77 patients who had a biomarker analysis for PD-L1, we looked at activity. There were 12 patients with EGFR mutations, [which] is a big number.

Usually [EGFR-mutant] tumors are low [expressors] for PD-L1, so I think we interpreted that [incorrectly,] that it was [only] the PD-L1–positive patients who were benefiting. That, I think, misled the plan of the trial around the primary end point and, in retrospect, I’m not surprised at all that it looks like the PD-L1–negative subgroup is the one that might benefit the most.

Liu: That’s an interesting point, we should just be excluding the driver-positive lung cancers. CheckMate 227 was a positive study, and this is an FDA-approved regimen [for which] we have long-term follow-up.

These data were presented at ASCO 2022 by Julie R. Brahmer, MD, MSc, [and] are the 5-year results. What we saw here is that the clear winner was dual checkpoint blockade outperforming nivolumab alone and outperforming chemotherapy alone. Those weren’t directly compared but nivolumab and ipilimumab were superior to chemotherapy with a hazard ratio for survival of 0.77.

The impressive piece here is long-term survival. We see it at 3 years: the 3-year rate of survival was 33% vs 22% with chemotherapy; the 4-year survival rate was 28% vs 18%; and the 5-year survival rate was 24% vs 14%. There’s not a whole lot of difference between the 3-year survival and 5-year survival [outcomes]. We really do see that flattening out [of the curve] and remember, there’s no chemotherapy involved in this. We have 1 of 4 patients still alive at 5 years in the PD-L1–positive group.

In the PD-L1–negative group, which was not the primary end point, we see significant benefit. In fact, the hazard ratios here [were] even better—0.65 for nivolumab/ipilimumab vs chemotherapy. One in 5 patients with PD-L1–negative disease [was] alive at 5 years [with nivolumab/ipilimumab]; however, the FDA approval does not include PD-L1–negative disease as part of the label. I agree that is perhaps where we see a bigger need, maybe even more benefit, with this.

Ready: One important part of the PD-L1negative design in CheckMate 227 is that, unlike a lot of the current trials where chemotherapy is the comparator, it’s not a standard of care anymore. Here, in the PD-L1–negative group we have a comparator arm of nivolumab plus chemotherapy, so we actually have in 1 trial a direct comparison of nivolumab/ipilimumab vs nivolumab/chemotherapy and we see an approximate 10% difference in survival at 3 years, 4 years, and 5 years...I think [those are] significant data that we don’t get in any of the other trials.

Liu: That’s a great point. It’s helpful to see these curves and how the [regimens] perform concurrently. When we look at 5-year survivors, the important point here is that among patients who are alive at 5 years with nivolumab/ipilimumab, the median PFS [progression-free survival] was 5 years. I would interpret this as saying the patients who are alive at 5 years in the nivolumab/ipilimumab arm never progressed.

Individuals in the chemotherapy arm who are alive at 5 years progressed within 9 months in the PD-L1–positive group and went on to some other type of immunotherapy. It’s really showing that it is the immunotherapy that’s driving things, [and] what we’re seeing now in our long-term survivors are steadily increasing numbers of treatment-free intervals where patients are alive and off therapy for 1, 2, or 3 years and climbing. That’s what we want—individuals who are alive and no longer needing any therapy. At some point we’re going to call that a cure.

Another option we have, although it is emerging, is looking at dual checkpoint blockade with chemotherapy. That’s the CheckMate 9LA regimen—nivolumab and ipilimumab long-term with chemotherapy. The difference here is the chemotherapy is only given for 2 cycles, so a very abbreviated course of chemotherapy, and this may be the best of both worlds. You’re getting that initial bump in response rate and PFS where the chemotherapy maybe gives you a little reassurance for individuals who have symptomatic or high-burden disease, but you don’t continue that chemotherapy.

Dr Ready, I don’t know how it is at Duke, but I know at Georgetown, my melanoma colleagues are not believers in the chemotherapy aspect. They think it’s going to prevent memory T-cell formation and they are colored by the biochemotherapy experience in melanoma where adding chemotherapy to IL-2 did not do anything.5

Lung cancer is a different disease, and we know from the [findings of other] studies that chemotherapy can play a role, especially in that PD-L1–negative group. This strategy allows us to avoid the chemotherapy long term and what we saw was a clear survival benefit in favor of the nivolumab/ipilimumab/chemotherapy arm. The limited course of chemotherapy had an OS [overall survival] benefit with a hazard ratio of 0.74. [In] the 3-year update also presented at 2022 ASCO by Luis Paz-Ares, MD, PhD, we saw an improvement in PFS with a hazard ratio of 0.7 and an improvement in response rate increasing from 25% to 38%.

We get that initial benefit of the chemotherapy and that long-term survival benefit with nivolumab/ipilimumab. When we look at the PD-L1–positive group we see a hazard ratio of 0.74 favoring the nivolumab/ipilimumab combination. In the PD-L1–negative group there was a hazard ratio of 0.67 favoring that nivolumab/ ipilimumab combination. It’s another chemoimmunotherapy combination but bridges those therapies.

We’re using dual checkpoint blockade in the maintenance setting but not really continuing that long-term chemotherapy. Dr Ready, I don’t know if this is a regimen that has found its way into your practice at all.

Ready: Yes, for patients with low PD-L1 scores and [who] I think...have neoantigens, are smokers, have high tumor mutational burden, or other factors [for which] I would be afraid to not give chemotherapy. That’s the type of scenario where I would use the CheckMate 9LA regimen.

Liu: We have a lot of different options and need to tailor them. When I think of dual checkpoint blockade there are different toxicities. Dr Ready, what adverse effects do you notice more in patients receiving dual checkpoint blockade? If we’re looking at adding CTLA-4, does that add any kind of toxicity dimension?

Ready: I think of colitis and pituitary inflammation with ipilimumab. I think of those coupled but then some other rare ones will just rear up when you add ipilimumab.

Liu: If you give enough immunotherapy, you start seeing rare adverse effects periodically and the key is recognition and a high degree of vigilance so we can intervene early. Colitis is something that we did see at very high rates with ipilimumab in the early studies.

We were still figuring out the dose and Dr Ready I know that you were involved in some of those dose-finding studies. There is a difference in the dosing for [ipilimumab] in lung cancer compared with melanoma, right?

Ready: Yes, in the CheckMate 012 trial we specifically tried the melanoma regimen in lung cancer [and] we proved that you cannot use the same [administration]. We systematically studied the ipilimumab dose to the point where we felt that we had the sweet spot between giving enough to stimulate the immune system but keep[ing] it at a tolerable level.

Liu: I agree. It is important for those of us who treat multiple diseases [to remember] the different doses. I know it seems counterintuitive but to me it makes a lot of sense because the immune system that allows melanoma to escape is very different from an immune system that allows NSCLC, small cell lung cancer, or thymic cancers to escape.

We know, for example, in thymoma that checkpoint blockade is much more toxic and that there are far more immune-related AEs [adverse events]. I don’t think it has to do with the cancer per se, I think it has to do with the state of the immune system that allows that cancer to slip through. The dosing is important there. When we do see colitis, again that is not prohibitive in terms of using those drugs. It just requires a lot of vigilance.

Ready: If you’re using an immune combination and you see a toxicity you think is related to ipilimumab you can stop it and often continue with nivolumab alone.

Stephen V. Liu, MD, is an associate professor of medicine at Georgetown University, and director of thoracic oncology and head of developmental therapeutics at the Georgetown Lombardi Comprehensive Cancer Center, in Washington, DC.

Neal E. Ready, MD, PhD, is a head and neck oncologist at Duke Cancer Center in Durham, North Carolina.


  1. Brahmer JR, Lee JS, Ciuleanu TE, et al. Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): results from CheckMate 227. J Clin Oncol. 2022;40(suppl 17):LBA9025. doi:10.1200/JCO.2022.40.17_suppl. LBA9025
  2. Paz-Ares LG, Ciuleanu TE, Cobo-Dols M, et al. First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients (pts) with metastatic non–small cell lung cancer (NSCLC): 3-year update from CheckMate 9LA. J Clin Oncol. 2022;40(suppl 17):LBA9026. doi:10.1200/ JCO.2022.40.17_suppl.LBA9026
  3. An investigational immuno-therapy trial of nivolumab, or nivolumab plus ipilimumab, or nivolumab plus platinum-doublet chemotherapy, compared to platinum doublet chemotherapy in patients with stage IV non-small cell lung cancer (NSCLC) (CheckMate 227). ClinicalTrials.gov. Updated May 25, 2022. Accessed July 29, 2022. https:// clinicaltrials.gov/ct2/show/NCT02477826
  4. A study of nivolumab and ipilimumab combined with chemotherapy compared to chemotherapy alone in first line NSCLC (CheckMate 9LA). ClinicalTrials.gov. Updated May 24, 2022. Accessed July 29, 2022. https://clinicaltrials.gov/ct2/show/NCT03215706
  5. Verma S, Petrella T, Hamm C, Bak K, Charette M; Melanoma Disease Site Group of Cancer Care Ontarios Program in Evidence-based Care. Biochemotherapy for the treatment of metastatic malignant melanoma: a clinical practice guideline. Curr Oncol. 2008;15(2):85-89.
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